Activation of the NAD⁺-Sirtuin Axis Protects Against Chronic Doxorubicin-Induced Subclinical Renal Tubular Injury Through Restoration of Mitochondrial Homeostasis and Suppression of Inflammation

Anthracyclines, including the drug doxorubicin, can lead to kidney problems later on, but the reasons behind this are not fully understood. To investigate this, researchers studied mice given low doses of doxorubicin over time and looked at whether this caused long-term harm to the kidneys' tubules. They also tested whether activating a certain biological pathway could help protect against this damage.

The mice received doxorubicin in small doses repeatedly, sometimes alongside a compound called resveratrol or nicotinamide mononucleotide, which activates the NAD-Sirtuin pathway. By examining the kidneys through various tests, the researchers found that even low doses of doxorubicin could cause damage to the kidney tubules, even if overall kidney function remained normal.

Using advanced imaging and analysis techniques, they discovered that the drug led to broken-down mitochondria in the tubular cells and a reduced ability to produce energy.

Furthermore, the study found that the drug increased levels of a specific protein linked to oxidative stress and triggered inflammatory processes in the kidneys. However, the researchers also observed that activating the NAD-Sirtuin pathway with resveratrol or nicotinamide mononucleotide could counteract these effects. It reduced mitochondrial damage, restored the balance of mitochondrial function, minimized protein modifications associated with oxidative stress, and dampened inflammation.

These findings suggest that chronic low-dose doxorubicin exposure can cause subtle kidney damage through mitochondrial dysfunction and inflammation. The study highlights the potential of targeting the NAD-Sirtuin pathway as a therapeutic strategy to protect against chemotherapy-induced kidney injury, offering hope for preventing long-term consequences of this common treatment.